Capecitabine-based chemotherapy in early-stage triple-negative breast cancer: a meta-analysis

Introduction The efficacy and safety of adjuvant capecitabine in early-stage triple-negative breast cancer remains undefined. A meta-analysis was conducted to elucidate whether capecitabine-based regimens could improve survival in early-stage triple-negative breast cancer (TNBC). Methods The current study searched Medline, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov proceedings up to 2023.9. Disease-free survival (DFS), overall survival (OS), and grade 3–4 adverse events (AEs) were assessed. Extracted or calculated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled. Results The capecitabine-based regimens showed significant advantages in DFS (HR = 0.81, 95% CI: 0.73–0.90; P <.001) and OS (HR = 0.75, 95% CI: 0.65–0.87; P <.001) from 12 randomized controlled trials (RCTs) with 5,390 unselected participants. Subgroup analysis of DFS showed analogous results derived from patients with lymph node negative (HR = 0.68, 95% CI: 0.50–0.92; P = .006) and capecitabine duration no less than six cycles (HR = 0.73; 95% CI: 0.62-0.86; P <.001). Improvement of DFS in the addition group (HR = 0.77, 95% CI: 0.68–0.87; P <.001) and adjuvant setting (HR = 0.79, 95% CI: 0.70–0.89; P <.001) was observed. As to safety profile, capecitabine was associated with more frequent stomatitis (OR = 5.05, 95% CI: 1.45–17.65, P = .011), diarrhea (OR = 6.11, 95% CI: 2.12–17.56; P =.001), and hand–foot syndrome (OR = 31.82, 95% CI: 3.23–313.65, P = .003). Conclusions Adjuvant capecitabine-based chemotherapy provided superior DFS and OS to early-stage TNBC. The benefits to DFS in selected patients with lymph node negative and the addition and extended duration of capecitabine were demonstrated.


Selection criteria
Inclusion criteria were as follows: (a) phase III RCTs of early BC involving TNBC; (b) RCTs contained a comparison of capecitabinebased chemotherapy against capecitabine-free regimens; (c) available HRs with 95% CIs for DFS and/or OS.RCTs published other than English were excluded.

Data extraction
Two reviewers (XL, JB) extracted data by search strategy independently.Discordance would be resolved by consensus.Information captured from RCTs included the following: trial name, authors, update year, study design, TNBC patients, baseline characteristics, chemotherapy schedules, median follow-up period, survival results (HRs and 95% Cis for DFS and/or OS), and grade 3-4 adverse events (AEs).

Quality assessment
The quality of studies was independently assessed using the Cochrane Risk Of Bias Assessment Tool (CROBAT), which consists of "random sequence generation," "allocation concealment," "blinding of participants and personnel," "blinding of outcome assessment," "incomplete outcome data," "selective reporting," and "other bias" (Figure S1).Publication bias was evaluated by Funnel plot and Egger's regression asymmetry test (21) (Figures S2-S4).

Statistical analysis
By the generic inverse variance method, the HRs and 95% CIs for DFS and/or OS in TNBC were pooled (22).The odds ratios (ORs) of grade 3-4 AEs were weighted and estimated.In addition, current analysis followed the intention-to-treat principle.We conducted subgroup analyses in accordance with (a) nodal status, (b) capecitabine duration, (c) adding or replacing capecitabine in chemotherapy, (d) adjuvant or neoadjuvant chemotherapy, (e) dosage of capecitabine, (f) the TNBC proportion, (g) combined chemotherapy regimen, (h) sequential or concomitant capecitabine, (i) study region, (j) menopausal status, (k) tumor size, (l) histological grade, (m) basal or nonbasal subtype, and (n) Ki-67 status.Heterogeneity among RCTs was evaluated by the Cochran Q statistics and I 2 test (23).When P < 0.10 or I 2 > 50%, we utilized the random-effect model.Otherwise, the fixed-effect model was used.Sensitivity analysis was conducted to assess the stability.Analyses were two-tailed with Stata 17.0 software.
There was no significant publication bias from the Funnel plot or Egger's test (Figures S2-S4).Sensitivity analysis indicated that no certain trial affected the pooled results (Figures S5, S6).
Flow diagram of the search process.

Discussion
There were several RCTs with conflicting results about capecitabine in early TNBC.Recently, the EA1131 and SYSUCC-001 trials provided updated outcomes with details about patient characteristics and treatment strategies (7,8).In addition, the FinXX trial updated overall survival on the basis of approximately 15-year follow-up of the patients (6).Therefore, it is reasonable to reevaluate the influence of capecitabine.As for metastatic TNBC, capecitabine had low response rates and limited activity in trials (23,24).Selecting appropriate patients may enhance treatment effects, since the mechanisms remained unclear.
Focusing on the association of capecitabine and early TNBC, there were two meta-analyses recently (18, 19).However, meta-analysis from Xun et al. did not extract data from the TACT2 trial, which should be included as well (14,18).In addition, the GAIN and GEICAM/2003-10 trials only consisted node-positive patients; in other words, they should be incorporated to the nodal status subgroup analysis as well (13, 15).Zhou et al. included trials more rigorously, so subgroup analysis performed with less information (19).
We conducted a comprehensive meta-analysis of 12 RCTs (full text) exploring the efficacy and safety of capecitabine-based chemotherapy.It significantly improved DFS and OS among 5,390 TNBC patients.Considering subgroup analysis, the survival Forest plot of pooled disease-free survival and overall survival for capecitabine-based regimens in early triple-negative breast cancer (A) Shows the results for pooled disease-free survival.(B) Shows the outcomes for pooled overall survival.benefits were observed in lymph node negative status, the addition, extended duration, and adjuvant setting of capecitabine.
Metastasis of lymph node contributes to higher risk for TNBC.We speculated that capecitabine would confer further extended survival on node-positive patients.Nevertheless, the result was paradoxical.It might be strong distinction of capecitabine on micro-metastatic and overt lesions.Targeting the immune escape metastasis mechanism, dormant tumor cells with a lower proliferation index were more sensitive to an antimetabolite drug.Similar to capecitabine, it is a DNA synthesis inhibitor (25).
Biomarkers determining which TNBC subtype favored most are also needed; for example, the PAM50 non-basal molecular subtype and the BRCA1-like DNA copy number (26,27).Extrapolation from studies of the last decade with long-term follow-up should be cautiously applied.The RCTs of individual survival benefits of capecitabine for node-positive patients are still needed.
Adjuvant capecitabine added to the anthracycline and taxane regimens had survival advantages for early TNBC, in favor of the synergism of docetaxel and capecitabine in preclinical models (28).The results verified the rationale of combination chemotherapy (29).Patients derived greater DFS from extended capecitabine duration (≥6 cycles), which means capecitabine could modulate antitumor immune and anti-angiogenesis properties through metronomic therapy (30).
Our study has limitations.First, populations with various characteristics contributed to the heterogeneity.The definition of ER-negative in the CBCSG010 and CREAT-X studies (<10%) did not align with others (<1%) (10,12).Second, the diverse chemotherapy regimens confounded the results and decreased robustness.Third, given no individual patient data available, the   details (age and intrinsic subtype) were incomplete, so it was hard to assess and select the subpopulation.

Conclusion
This meta-analysis showed that capecitabine-based regimens significantly improved both DFS and OS in early-stage TNBC.There was a substantial improvement for DFS in the groups with lymph node negative status, the adjuvant, addition, and longer duration (≥6 cycles) of capecitabine to standard chemotherapy.

3
FIGURE 3 Forest plot of disease-free survival for adjuvant capecitabine in subgroups with heterogeneous results.(A) Shows disease-free survival in the nodal positive or negative subgroup.CIBOMA/2004-01(1-3) denotes subgroup with one to three positive lymph nodes.CIBOMA/2004-01(≥4) is defined as subset with no less than four positive nodes.(B) Shows disease-free survival by capecitabine duration (≥6 cycles or <6 cycles).(C) Shows diseasefree survival according to the addition or replacement of capecitabine.(D) Shows disease-free survival depending on capecitabine accounting for adjuvant or neoadjuvant chemotherapy.

TABLE 1
Study characteristics.